Is BFSP1 p.Gln76Pro (c.227A>C) pathogenic?

BFSP1 p.Gln76Pro (c.227A>C) is classified Uncertain significance in BFSP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-08). AlphaMissense: ambiguous (0.516); Very rare (popmax 0.00358%, amr); Associated with cataract 33.

What condition is associated with BFSP1 p.Gln76Pro (c.227A>C)?

BFSP1 p.Gln76Pro (c.227A>C) is associated with cataract 33 (ClinVar).

How common is BFSP1 p.Gln76Pro (c.227A>C) in the general population?

BFSP1 p.Gln76Pro (c.227A>C) is very rare (popmax 0.00358%, amr) (gnomAD).

What do computational predictors say about BFSP1 p.Gln76Pro (c.227A>C)?

AlphaMissense predicts ambiguous (score 0.516) — an in-silico prediction, not a clinical call.

BFSP1 p.Gln76Pro

c.227A>C · VCV3716700

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.516 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00358%, amr)

Conditions

cataract 33

Computational evidence

Protein change
AlphaMissense	0.516	ambiguous
REVEL	0.632	indeterminate
SaProt	LLR -12.40	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP -1.5, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 37 kb · p 0.4 · regional, not allelic
Overall
CADD	24.8	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00358% Admixed American · 1/27,920 alleles

Filtering AF 0.000204% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000134%

Overall 0.000583% 7/1,201,646 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00358%	27,920
European (non-Finnish)	0.000568%	175,965

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: BFSP1
Protein: p.Gln76Pro
Coding: c.227A>C
MANE Select: NM_001195
Type: single nucleotide variant
Location: chr20:17531103 (GRCh38)
Gene constraint: LOEUF 1.371 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.66
Residue 76: the if rod domain; the 'linker 1' region

Full BFSP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

cataract 33 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

BFSP1 p.Ala643Thr Uncertain significance ★★ ⚠ same condition
BFSP1 p.Arg560Cys Uncertain significance ★★ ⚠ same condition
BFSP1 p.Arg69Trp Uncertain significance ★★ same condition
BFSP1 p.Asp19Asn Uncertain significance ★★ ⚠ same condition
BFSP1 p.Gln294Arg Uncertain significance ★★ ⚠ same condition
BFSP1 p.Gly46Trp Uncertain significance ★★ ⚠ same condition
BFSP1 p.Ile271Thr Uncertain significance ★★ ⚠ same condition
BFSP1 p.Leu68Phe Uncertain significance ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/bfsp1-p-gln76pro (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown